Paradigms of Wound Healing and Fibrosis in the Eye

摘要/项目摘要 眼睛的免疫豁免是因为需要保持血管系统不受中心光路的影响 会损害视力。因此，眼睛的器官和组织，如角膜，已经发展出替代 免疫监视机制，以保护它们，并响应损伤或组织发病。在 中枢神经系统，新的免疫监视适应已被发现用于保护和修复 表现出一种免疫静止的状态。在可以耐受外来抗原的角膜中，有 免疫细胞在角膜、房水和泪液的周边区域监视它。这个 在免疫监视和保护方面，晶状体一直是一个谜。我们现在展示这一点，就像其他 组织，晶状体已经发展出免疫监视机制，以终生保护它，并 应对压力和伤害，同时保持透明度。由于免疫功能失调 监测与纤维化的发展密切相关，有可能是免疫细胞与 晶状体可能是导致白内障和后囊混浊(PCO)的未知原因。 我们已经在晶状体中发现了常驻免疫细胞(β2整合素/CD45)，它们在 模拟白内障手术，对创面的再生修复具有重要作用。这些细胞是 容易从这一角色中转移，并被诱导获得一种肌成纤维细胞表型，即细胞类型 这是纤维性PCO的基础。常驻免疫细胞在发育过程中首先出现在晶状体中，交付 通过血管膜，一个围绕着正在发育的晶状体的血管系统；然而，这个血管系统 出生后就会退化。据推测，没有活跃的免疫细胞来源可以监视 并在动态平衡和应对压力、损伤或发病时保护成人晶状体。然而， 我们发现 对晶状体发育不全(N-cad∆晶状体小鼠)或角膜清创伤的反应，一种外源性免疫 监测机制被激活，导致免疫细胞向晶状体募集。这些免疫 细胞在睫状体和晶状体之间移动，穿过连接它们的睫状带，在没有细胞的情况下 脉管系统的。随着时间的推移，这些免疫细胞可以获得肌成纤维细胞表型并导致晶状体 不透明。对这些N-cad∆晶状体小鼠眼睛的研究也表明，对晶状体有免疫反应。 中央角膜、玻璃体和视网膜发育不全。 我们将以这些发现为基础，通过三个具体的目标来阐明外源性免疫细胞如何 能够到达晶状体，免疫系统是如何被激活以保护晶状体对角膜的反应 损伤和保护角膜以应对晶状体发育不全，以及免疫细胞如何监视晶状体 对其损伤/发病机制的反应，或对其他组织的损伤/发病，可能导致白内障和后发性白内障。

Abstract/Project Summary Immune privilege of the eye results from the need to keep vasculature from the central light path where it would impair vision. Therefore, organs and tissues of the eye like the cornea, have developed alternative mechanisms of immune surveillance to protect them and in response to injury or tissue pathogenesis. In the CNS, novel immune surveillance adaptations have been discovered for protection and repair that demonstrate a state of immune quiescence. In the cornea, which can tolerate foreign antigens, there are immune cells that surveille it in the peripheral regions of the cornea, the aqueous humor, and the tears. The lens has remained an enigma in terms of immune surveillance and protection. We now show that, like other tissues, the lens has developed mechanisms of immune surveillance to protect it throughout a lifetime and to respond to stresses and injury while maintaining its transparency. Since dysregulation of immune surveillance is tightly linked to development of fibrosis, it is possible that the immune cells that associate with the lens may be an unexplored cause of cataract and posterior capsule opacification (PCO). We have discovered resident immune cells (β2 integrin/CD45+) in the lens, that are activated upon mock cataract surgery and have essential functions in regenerative repair of the wound area. These cells are susceptible to being diverted from this role, and induced to acquire a myofibroblast phenotype, the cell type that underlies fibrotic PCO. The resident immune cells first appear in the lens during development, delivered by the tunica vasculosa, a vasculature that surrounds the developing lens; however, this vasculature degenerates after birth. It was assumed that there are no active sources of immune cells that could surveille and protect the adult lens during homeostasis and in response to stress, injury, or pathogenesis. However, we discovered that in response to lens dysgenesis (N-cad∆lens mice) or corneal debridement wounding, an extrinsic immune surveillance mechanism is activated resulting in the recruitment of immune cells to the lens. These immune cells move between the ciliary body and the lens across the ciliary zonules that connect them, in the absence of a vasculature. Over time, these immune cells can acquire a myofibroblast phenotype and lead to lens opacity. Studies of eyes from these N-cad∆lens mice also revealed that there is an immune response to lens dysgenesis in the central cornea, vitreous, and retina. We will build on these findings in three specific aims expected to elucidate how extrinsic immune cells are able to travel to the lens, how the immune system is activated to protect the lens in response to corneal injury and to protect the cornea in response to lens dysgenesis, and how immune cells that surveille the lens in response to its damage/pathogenesis, or that of another tissue, may lead to cataract and PCO.